Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In serious cases, arrhythmias may give rise to ventricular fibrillation which can cause sudden death.
According to the classification of Vaughan-Williams, there are four distinct classes of antiarrhythmic agents. Class I antiarrhythmic agents are those agents which provide for sodium channel blockade, including those compounds which exert a membrane stabilizing effect. Exemplary of this class of compounds are quinidine, procainamide, disopyramide, lidocane, tocainide, flecainide and propafenone. Class II antiarrhythmic compounds are agents which block sympathetic activity. Exemplary of this class of compounds are propranolol and acebutolol. Class III antiarrhythmic agents are compounds which prolong the effective refractory period without altering the resting membrane potential or rate of depolarization. Compounds such as amiodarone, bretylium and sotalol are considered to be in this class. Class IV antiarrhythmic agents are effective in calcium channel blockade. Exemplary of this class of compounds are diltiazem and verapamil. Further definition of these classes can be found in Pharma Projects, section C1B, May 1993.
Though various antiarrythmic agents are now available on the market, agents which exhibit both satisfactory effects and high safety profiles have not been marketed, For example, antiarrythmic agents of Class I, which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax), are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety as they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Antiarrythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drugs in this class are limited. Drugs such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which can cause cardiac depression and is therefore contraindicated in certain susceptible patients. Amiodarone is also severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillations. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
U.S. Pat. No. 5,658,901 discloses novel 2-oxo-1,4-benzodiazepines which are potent Class III agents. Compounds in this patent, while extremely potent, display extended half lives in animals, resulting in a high potential for toxicity. The compounds of the present invention show a decreased half-life in animals.
U.S. Pat. Nos. 5,595,900 and 5,631,251 disclose additional antiarrhythmic benzodiazepines.